Clinical trials testing type 1 insulin-like growth factor receptor (IGF-1R) inhibitors failed in endocrine- sensitive and resistant breast cancer. These trials failed to include targeting of the insulin receptor (IR) and essential component of the IGF signaling system. Further, data from patients with endocrine resistant breast cancer showed that insulin receptor (IR) is more highly expressed in breast cancer cells than IGF- 1R. While it may seem futile to target IR, data show the fetal isoform of IR, IR-A, is more highly expressed than the adult isoform IR-B in cancers. Thus, it may be possible to create a cancer specific inhibitor of a highly expressed receptor for breast cancer treatment. We hypothesize that targeting of IR alone and in combination with other breast cancer therapeutics will be an effective therapy. Moreover, specifically targeting IR-A will be cancer specific with little impact on glucose homeostasis. To test this hypothesis, we propose three specific aims: 1) Engineer IR-A antagonists using small synthetic protein ligands via directed evolution; 2) Demonstrate IR-A regulation of the breast cancer malignant phenotype compared to IR-B and define a mechanism; and 3) Evaluate the efficacy of an IR-A specific antagonist, our existing IR-A and IR-B antagonists, and IGF-1R antagonists alone and in combination in breast cancer model systems Major advances in breast cancer have been the direct result of understanding and targeting key growth regulatory signals. Based on the failure of trials targeting the IGF-1R, we now have clear evidence that IR play a critical role in breast cancer development. Just as we were at the among the first to develop IGF-1R inhibitors, we have shown that IR inhibitors also may be used to target breast cancer. Completion of this proposal will further the development of new targeted breast cancer therapies. Cancer specific IR may be accomplished by development of an IR-A specific inhibitor. Given the growing number of women with hyperinsulinemia, creating a cancer specific inhibitor of IR could have significant impact.